Some two hundred pharmocologically active alkaloids have now been identified in extracts of frog skins. The batrachotoxins (steroidal) are potent activators of voltage-dependent sodium channels. Antagonism of binding of radioactive batrachotoxinin-A benzoate to brain synaptoneurosomes provides a rapid assay for local anesthetic activity of a wide range of drugs. Histrionicotoxins (spiropiperidines) block voltage dependent sodium and potassium channels and thenicotinic receptor-channel complex. Structure activity for natural and synthetic histrionicotoxins at the nicotinic receptor-channel complex has been assessed using binding of radioactive perhydrohistrionicotoxin as a probe. Pumiliotoxins (6-alkylidene-8-hydroxy-8-methylindolizidines) and allopumiliotoxins (7-hydroxypumiliotoxins) enhance evoked release of acetylcholine and augment direct of indirect-evoked muscle contraction in neuromuscular preparations and have positive chronotropic and inotropic effects in heart. These effects are markedly dependent on structure and appear due to alkaloid-induced augmentation of release of calcium from intracellular storage sites. Gephyrotoxins (perhydrobenzoindolizidines), like the histrionicotoxins, block the nicotinic receptor-channel complex. Gephyrotoxin appears to not only block the open channel but to acclerate desensitization of the receptor channel complex. Certain local anesthetics, such as bupivacaine, also block the nocotinic receptor-channel complex through interaction at histrionicotoxin-sensitive sites.